This is a proposal to continue our Cystic Fibrosis (CF) Research and Translation Core Center at the University of California, San Francisco and collaborating institutions. The focus of our Core Center remains the discovery and evaluation of novel small-molecule therapies for CF. The Core Center will fund five Cores to support the activities of three Pilot Projects and 25 CF-related projects. The Core directors are experienced CF investigators with recognized expertise in their areas of investigation and a history of productive collaboration. The Cores include: High-Throughput Screening (Core A), Cell & Tissue Models (Core B), Synthesis (Core C), CF Cell & Tissue Bioassays (Core D), and CF Biochemistry (Core E). Projects to utilize the Cores fall in three areas: (i) Ion Channel-Related CF Drug Targets, (ii) Non-Ion Channel CF Drug Targets, and (iii) Translational Research: CF Therapeutic Strategies and Targets. Small-molecule therapies to be developed in our Core Center have potential applications in treatment of the underlying defect in CF and in treating the causes and manifestations of lung disease in CF. The general goal of the research to be enhanced by the Core Center is to develop new small-molecule therapies for CF that can be translated into the clinic.